Effective treatment of central apnea remains elusive. This project is focused on identifying mechanistic pathways to guide future therapeutic interventions for central sleep apnea (CSA) based on the strong premise that multi-modality therapy - aiming to normalize respiration- is the requisite path to mitigating the long-term adverse consequences of CSA. Our central hypothesis is that CSA reflects a combination of physiologic perturbations and may require combined modality therapy targeting different parts of the ventilatory feedback loop. Our proposed studies will test combination therapies, including PAP plus a pharmacological agent. This will also increase the clinical relevance of the proposed studies since PAP therapy is typically prescribed as the initial treatment of CSA. We propose to modify CSA propensity via three distinct physiologic pathways: 1) decreasing loop gain with oxygen and/or acetazolamide, 2) decreasing ventilatory overshoot by dampening respiratory arousals with a hypnotic agent, and 3) elevating the ventilatory motor output with a serotonergic agent. To ensure clinical relevance, we will focus on the two most common types of CSA: 1) heart failure with reduced ejection fraction (HFrEF) and 2) opioid use, using stratified randomization to balance the number of subjects in each arm of each experiment. To achieve the objectives of this proposal, we will test the following three specific aims. Specific Aim (1) is to determine the effect of combination therapy aiming to dampen chemoreceptor sensitivity AND decreasing plant gain. We hypothesize that combined therapy with PAP, acetazolamide and oxygen will be superior to each intervention alone in reducing CAHI and the CO2 reserve during sleep in patients with central sleep apnea. Specific Aim (2) is to determine the effect of decreasing respiratory-related arousals on the propensity to develop central apnea. We hypothesize that administration of PAP and zolpidem, will decrease respiratory-related arousals, CAHI and the CO2 reserve during sleep in patients with CSA compared to placebo. Specific Aim (3) is to determine the effect of augmenting serotonin A1 receptor activity on breathing during sleep. We hypothesize that administration of PAP and buspirone, a serotonin A1 receptor agonist; will reduce the propensity to central apnea during sleep in Veterans with central sleep apnea. This Novel project seeks to identify physiologic pathways that can, in combination with PAP therapy, improve the effectiveness of treatment for patients with CSA. The proposed studies are innovative, feasible and will provide a much-needed roadmap for future clinical trials that are likely to transform the care of central apnea in Veterans.